Three major worldwide foci of the fatal parasitic disease visceral leishmaniasis (cVL) occur in India, Sudan and Brazil. 80-90% of human infections are sub-clinical or asymptomatic, usually associated with strong cell-mediated immunity which can result in a positive skin-test delayed type hypersensitivity test (DTH+) to leishmanial antigen. The goal of this project is to understand why individuals with the same exposure to leishmaniasis experience different outcomes of infection. Prior genetic studies of cVL have been underpowered to examine candidate genes with confidence, or to find all genes influencing the complex phenotypes of cVL or DTH response. We have now accumulated sample sizes of sufficient power to carry out hypothesis-driven candidate gene allelic association studies with confidence, and to perform SNP-chip based genome-wide association scans (GWAS). Indeed, primary SNP-chip based genome-wide association scans (GWAS) of cVL from India and cVL/DTH response in Brazil will be completed during 2008/9. Aims of this RO1 are: 1. To test the hypothesis that candidate genes (SLC11A1, IL4-LECT2/TGFBI, HLA) determine susceptibility to cVL and to asymptomatic infection (DTH+) using dense tag-SNPs, with sample sizes that are sufficiently powered to study these complex disease phenotypes. 2. To identify novel susceptibility genes and associated functional etiological variants by validating the positive results of the population-based primary GWAS being performed on 1000 cVL cases and 1000 controls from India, using dense tag-SNP family-based allelic association tests that control for ethnicity in 1217 extended cVL families, re-sequencing, bioinformatic analysis, and mRNA and protein expression analysis. 3. To identify novel susceptibility and resistance genes and associated functional etiological variants, by validating results of the family-based primary GWAS being performed on individuals with cVL (626), DTH+ (1160) or DTH- (900) phenotypes in Brazilian families, using dense tag-SNP family-based allelic association, re-sequencing, bioinformatic analysis, and mRNA and protein expression analysis. A major aim of genetic studies is to identify genes/mechanisms/pathways that contribute to the pathogenesis of disease. Pathway analysis of genes validated by the above studies will be used to define immunological, biochemical and molecular pathways that are important in the pathogenesis of cVL. This study has the potential to demonstrate that the same molecular pathways are important across different geographic regions/Leishmania species, and also to discover specific genetic polymorphisms that provide population-specific susceptibility to disease. The study could seed novel functional studies that could translate into future disease intervention measures.